Paraquat and MPTP alter microRNA expression profiles, and downregulated expression of miR‐17‐5p contributes to PQ‐induced dopaminergic neurodegeneration

Abstract

Recent evidence indicates that microRNAs (miRNAs) play a key role in neurodegenerative diseases. However, the toxic effects of paraquat (PQ) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on miRNA expression profiles in dopaminergic neurons have not been investigated. In the present study, we used microarray analysis to show that PQ and MPTP induce alterations of miRNA expression in neuro-2a cells. The results reveal that treatment with 300 μm PQ caused miRNA deregulation, such that 60 miRNAs were upregulated and 228 miRNAs were downregulated. Following treatment with 300 μm MPTP, a total of 576 miRNAs were dysregulated, of which 506 were upregulated and 70 were downregulated. Alterations in the expression of miR-17-5p, miR-210-3p, miR-374-5p, miR-378-3p and miR-503-5p were verified by real-time quantitative reverse transcriptase polymerase chain reaction. Moreover, overexpression of miR-17-5p in Neuro-2a cells enhanced cell proliferation, suppressed apoptosis and promoted S phase transition of the cell cycle after PQ treatment. Taken together, our study demonstrates that characteristic changes in miRNA expression profiles occur after PQ and MPTP treatment, which suggests that miRNAs may be involved in the development of PQ- and MPTP-induced neurodegeneration. Downregulated miR-17-5p expression contributes to PQ-induced dopaminergic neurodegeneration.

The microRNA-17 ~ 92 Family as a Key Regulator of Neurogenesis and Potential Regenerative Therapeutics of Neurological Disorders

“…The misexpression of miR-25 can inhibit proliferation and induce cell apoptosis in AD mouse primary hippocampal cell culture, suggesting miR-17~92 may possess much more complex functions in the pathogenesis of neurodegenerative diseases than previously thought. Furthermore, in an in vitro PD model, the expression levels of miR-17 are significantly reduced, contributing to dopaminergic neurodegeneration and proliferation attenuation [33]. Besides, being a well-recognized primary oncogenic miRNA family, the expression of miR-17~92 is dramatically up-regulated in glioma tissues.…”

“…Due to its importance in neurogenesis regulation, miR-17~92 family is widely involved in the pathogenesis of neurobiological disorders. For instance, the decay and over-synthesis of miR-17~92 are linked to neurogenesis deficiency in neurodegenerative diseases and uncontrolled cell growth in glioma, respectively [33,34]. Conversely, miR-17~92 family can also be utilized as potential regenerative therapeutics to t r e a t b r a i n i n j u r y v i a s t i m u l a t i n g e n d o g e n o u s neurogenesis [35].…”

The latest progress on miR‐374 and its functional implications in physiological and pathological processes

“…In recent years, research on the degenerative changes of the nervous system by miRNAs has grown. Wang et al found that PQ‐ and MPTP‐treatment inhibited the expression of miR‐374‐5p ( P < 0.01) in Neuro‐2a cells. Yet, miR‐374‐5p was not associated with several biological processes including regulation of DNA dependent transcription and RNA metabolic processes in the pathogenesis of Parkinson's disease.…”

Reactive oxygen species regulate miR‐17‐5p expression via DNA methylation in paraquat‐induced nerve cell damage

“…The miRNAs are also an important epigenetic regulator of gene expression, and the association of abnormal DNA methylation with silencing individual miRNA genes has been found in many cancer types, 26,27 so we would like to investigate the changes in PQ‐induced miRNA expression, whether there is a link between miRNA and DNA methylation. Our pre‐miRNA chip results show that PQ can cause changes in miRNA expression profiles in neuro‐2a cells 3 . qRT‐PCR result verified that PQ downregulated miR‐17‐5p level in neuro‐2a cells (Figure 5).…”

“…In our previous study, we found that PQ could cause nerve cell damage and reduce the expression of miR‐17‐5p in neuro‐2a cells. And the downregulated miR‐17‐5p is at least partly involved in PQ‐induced neurotoxicity mechanisms and contributes to proapoptotic effects 3 . What is the way in which PQ induces a decrease in miR‐17‐5p expression and causes neuronal damage?…”